Cloning and expression of the human N-acetylglutamate synthase gene

Caldovic, Ljubica; Morizono, Hiroki; Panglao, Maria; Gallegos, Rene; Yu, Xiaolin; Shi, Dashuang; Malamy, Michael H.; Allewell, Norma M.; Tuchman, Mendel

doi:10.1016/s0006-291x(02)02696-7

Cited by 77 publications

(86 citation statements)

References 18 publications

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“…Clinical syndromes have been described involving deficiencies of five urea cycle enzymes and three related cofactors and transporters [1][2][3]. The most common of these conditions, ornithine transcarbamylase deficiency (OTCD), is the only X-linked disorder, with an incidence of 1:70,000 [4].…”

Section: Introductionmentioning

confidence: 99%

1H MRS allows brain phenotype differentiation in sisters with late onset ornithine transcarbamylase deficiency (OTCD) and discordant clinical presentations

Gropman

Seltzer

Sawyer

et al. 2008

Molecular Genetics and Metabolism

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We used 1 H MRS to evaluate brain metabolic differences in sisters with partial ornithine transcarbamylase deficiency (OTCD) who had discordant clinical symptoms and urea synthetic capabilities to assess whether a brain biomarker of partial OTCD correlated with urea synthetic ability and clinical severity. We performed single voxel 3.0T 1 H MRS in two adult sisters with partial OTCD, one symptomatic and one asymptomatic, in a stable medical state and compared it to one age matched adult control, as well as data collected on an additional 13 subjects with partial OTCD and 12 controls. Data from voxels placed in frontal and parietal white matter (FWM, PWM), posterior cingulate gray matter (PCGM), and thalamus (tha), were corrected for partial volume and analyzed using "LCModel". All three subjects as well as the symptomatic mother of the two sisters, had neurocognitive testing, plasma ammonia levels, plasma amino acid, and urine organic acid analysis. Previous urea synthetic capabilities had been measured by stable isotope analysis. We found IQ scores to be inversely related to symptoms. Decreased myoinositol (mI) identified OTCD subjects, even the sister who is asymptomatic, in the posterior parietal white matter and frontal white matter. Brain metabolism is impaired in partial OTCD. Abnormal metabolism in apparently asymptomatic OTCD females may provide an explanation for neurocognitive impairments previously reported. The concentration of mI seen on 1 HMRS in PWM and FWM in this family could be used to deduce clinical symptomatology and may serve as a non invasive marker of brain liability in OTCD.

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Section: Introductionmentioning

confidence: 99%

1H MRS allows brain phenotype differentiation in sisters with late onset ornithine transcarbamylase deficiency (OTCD) and discordant clinical presentations

Gropman

Seltzer

Sawyer

et al. 2008

Molecular Genetics and Metabolism

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“…The conserved domain of human and mouse NAGS had lower specific activity suggesting that the variable domain either enhances catalytic activity or stabilizes the NAGS protein. Enzymatic activities of recombinant proteins increased two to sixfold in the presence of 1 mM arginine [12,14].…”

Section: Enzyme Characterizationmentioning

confidence: 99%

“…NAGS is primarily expressed in liver and small intestine, tissues in which CPSI is also exclusively expressed. Interestingly, a low level of expression is also detectable in kidney, testis, and spleen which could indicate other roles for NAGS beyond providing an essential cofactor for CPSI [12,14].…”

Section: Identification and Cloning Of The First Mammalian Nags Genementioning

confidence: 99%

“…Human NAGS is synthesized as a preprotein of 534 amino acids [12]. Because the enzyme is localized to the mitochondria, it was assumed that the N-terminal portion contains a targeting peptide that is subsequently cleaved.…”

Section: Protein Sequencementioning

confidence: 99%

“…A rapid and specific stable isotope LC-MS method for measuring NAG has also been developed to quantify NAGS activity [12][13][14][15], which has been used in the studies described herein.…”

Section: Introductionmentioning

confidence: 99%

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Mammalian N-acetylglutamate synthase

Morizono

Caldovic

Shi

et al. 2004

Molecular Genetics and Metabolism

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N-Acetylglutamate synthase (NAGS, E.C. 2.3.1.1) is a mitochondrial enzyme that catalyzes the formation of N-acetylglutamate (NAG), an essential allosteric activator of carbamylphosphate synthetase I (CPSI). The mouse and human NAGS genes have been identified based on similarity to regions of NAGS from Neurospora crassa and cloned from liver cDNA libraries. These genes were shown to complement an argA-(NAGS) deficient Escherichia coli strain, and enzymatic activity of the proteins was confirmed by a new stable isotope dilution assay. The deduced amino acid sequence of mammalian NAGS contains a putative mitochondrial-targeting signal at the Nterminus. The mouse NAGS preprotein was overexpressed in insect cells to determine posttranslational modifications and two processed proteins with different N-terminal truncations have been identified. Sequence analysis using a hidden Markov model suggests that the vertebrate NAGS protein contains domains with a carbamate kinase fold and an acyl-CoA N-acyltransferase fold, and protein crystallization experiments are currently underway. Inherited NAGS deficiency results in hyperammonemia, presumably due to the loss of CPSI activity. We, and others, have recently identified mutations in families with neonatal and late-onset NAGS deficiency and the identification of the gene has now made carrier testing and prenatal diagnosis feasible. A structural analog of NAG, carbamylglutamate, has been shown to bind and activate CPSI, and several patients have been reported to respond favorably to this drug (Carbaglu®).

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Disorders of the Metabolism of Amino Acids and Related Compounds

Shih¹,

Mandell²

2009

Genetic Disorders and the Fetus

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Cloning and expression of the human N-acetylglutamate synthase gene

Cited by 77 publications

References 18 publications

1H MRS allows brain phenotype differentiation in sisters with late onset ornithine transcarbamylase deficiency (OTCD) and discordant clinical presentations

1H MRS allows brain phenotype differentiation in sisters with late onset ornithine transcarbamylase deficiency (OTCD) and discordant clinical presentations

Mammalian N-acetylglutamate synthase

Disorders of the Metabolism of Amino Acids and Related Compounds

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